`CECIL
`3
`Texthook —
`
`
`22" Edition
`
`EDITED BY
`
`Lee Goldman, MD
`
`Julius R. Krevans Distinguished Professor and Chair
`Departmentof Medicine
`Associate Dean for Clinical Affairs
`University of California, San Francisco, School of Medicine
`San Francisco, California
`
`Jackson Professor of Clinical Medicine
`Harvard Medical School
`Chief, Medical Service
`Massachusetts General Hospital
`Boston, Massachusetts
`
`“ae —s al
`VOLUME 2
`
` *
`
`[seefa2
`
`i 1r
`
`R
`wh
`eye
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`& anaft
`
`SAUNDERS
`|
`An Imprint of Elsevier
`
`
`MPI EXHIBIT 1129 PAGE 1
`
`
`
`k
`SAUNDERS
`An Imprintof Elsevier
`
`The Curtis Center
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`Philadelphia, Pennsylvania 19106
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`0-7216-9652-%
`CECIL TEXTBOOK OF MEDICINE, 22ND EDITION
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`1971, 1963, 1959, 1955, 1951, 1947,
`International Edition
`1979, 1975,
`A
`Copyright © 2004, 2000, 1996, 1991, 1988, 1982,
`1043, 1040, 1937, 1933, 1930, 1927, Elsevier Inc. All rights reserved,
`Copyright renewed 1991 by Paul Beeson.
`Copyright renewed 1979 by Russell L. Cecil and Robert F Been seek
`Copyright renewed 1987, 1975, 1971, 1965, 1961, 1958, 1955 by
`Els
`:
`r 11, “The Periodic
`Thefollowing chapters are in the public domain (except borrowedfiguresHi akbyscile Chanter 29,
`Health Examination,” by David Atkins; Chapter 16, “Immunization, atte i er ay ete hel Bistrais:
`“Pain,” by Mitchell B. Max; Chapter 34, “Complementary and Alternative Me Tae a a eeaoa:
`Chapter 55, “Heart Failure: Pathophysiology and Diagnosis,’ by Barry M. Mass a
`Pp
`Neo faaieebe
`Endocrine Tumors,” by Robert T. Jensen; Chapter 198, “Lung Cancer and Other
`Pu eet eee *
`York E. Miller; Chapter 224, “Wilson's Disease,” by Stephen G. Kaler; Chapter 257,
`inera a
`Homeostasis,” by StephenJ, Marx, Chapter 260, “The Parathyroid Glands, Peeee aah
`Hypocalcemia,” by Allen M. Spiegel; Chapter 272, “Mastocytosis,” by Dean D. Metca ie;
`: ae fi ieee
`“Introduction to Bacterial Disease,” by David A. Relman; Chapter 309, “Rheumatic Fever, by Alan L. Bisno;
`Chapter 314,“Infections Caused by Haemophilus Species," by Michael 5. Simberkoff, Chapter 317,
`“Diphtheria,” by Roland W.Sutter, Chapter 373, “Enteroviruses,” by Michael N. Oxman, Chapter 374,
`“Viral Gastroenteritis,” by Albert Z. Kapikian; Chapter 378, “Introduction to Mycoses,” by Carol A.
`Kauffman; Chapter 379, “Histoplasmosis,” by Carol A. Kauffman; Chapter 381, “Blastomycosis, by CarolA.
`Kauffman; Chapter 382, “Paracoccidioidomycosis,” by Carol A. Kauffman; Chapter 383, “Cryptococcosis,
`by Carol A. Kauffman; Chapter 384, “Sporotrichosis,” by Carol A. Kauffman; Chapter 385, “Candidiasis,” by
`Carol A, Kauffman; Chapter 394, “American Trypanosomiasis (Chagas’ Disease),” by Franklin A. Neva,
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`Library of Congress Cataloging-in-Publication Data
`Cecil textbook of medicine / edited by Lee Goldman, Dennis Ausiello—22nd ed
`p. ; cm.
`Includes bibliographicalrefere:
`ISBN 0-7216-9650-X
`aes Bia
`1. Internal medicine.
`1. Title: Textho Ik
`of
`1881-1965.
`Ill. Goldman,Lee, MD.
`1V Oe I. Cecil, Russell L. (Russell La Fayette),
`[DNLM:1, Medicine. WB 100 C3888 2004, |
`RC46.C423 2004
`616—de21
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`ExecutivePublisher, Global Medicine: Kim Murphy
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`1129 PAGE2
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`
`MPI EXHIBIT 1129 PAGE 2
`
`
`
`933] OBESITY
`
`Michael D. Jensen
`
`Chapter 233 Obesity|1339
`88cm or 35 inches for women) is considered an additional indica-
`tion of risk for overweight and obesity. This measure is primarily
`relevantto disease risk in overweight and class 1 obesity categories,
`however.
`In. overweight
`individuals, a large waist circumference
`changes therelative risk from “increased” (relative to someone with
`a normal BMI) to “high,” In class | obesity, a large waist circumfer-
`ence increases the risk of disease from “high” to “very high.” A large
`waist circumference does notaffect disease risk in those persons with
`class 2 or class 3 obesity,
`
`Prevalence
`
`
`
`sasees|g/BUORMINN
`
`ity is the most common nutritional disorder in the Unite
`Of,costing more that $100 billion per year in healthiest
`expenses. Most physicians do Notreceive specific training in the eval-
`‘ation and management of obesity despite the fact thai more than
`half the patients theyencounter are likely to be overweight or ohese.
`Although progress has been made in understanding the pathophysi-
`ology and treatment ofobesity, it nonetheless remainsa dificult disease
`to treat, The safest and mosteffective treatment approaches (lifestyle
`and behavior modification) are not those commonly employed by
`physicians.
`
`The numberof overweight and obese adults in the United States
`has increased dramatically over the past 20 years.It is estimated that
`approximately 60% ofadult Americansareeitheroverweightor obese.
`Approximately 60% of U.S. men and 51% of U.S. women are over-
`weightor obese. It should be noted, however, that a preater percent-
`age ofwomen are obese than men, whereas a largerpercentage ofmen
`are overweight than women. There are substantial differences in the
`prevalence of obesity by age, race, and socioeconomicstatus, The
`prevalenceof obesity in adults tends torise steadily from ages 20 to
`60 years but does notincrease and,in [act, begins to decrease in later
`years. It has been estimated that almost 75% of men aged 60 to 69
`years in the United States have a BMIofgreater than 25. Theincrease
`in mean BMI with age may not be as muchofa threat to population
`health as mightfirst be anticipated, Whileitis true that youngadults
`with BMIs in the lowerpart of the normal range havethe lowest mor-
`tality rates, this changes with age. The BMIassociated with the lowest
`mortality rates is actually at or somewhat above 25kg/m’ for
`those in their 60s and 70s. Clearly, weight recommendations for a
`given individual depend on whether adverse health consequences
`associated with obesity have developed.
`The differences in overweight and obesity between Alrican-
`Americans, Mexican-Americans, and European-Americans are not
`subtle. African-American women and Mexican-Americans of both
`sexes have the highestrates of overweight and obesity in the United
`States. Wheninterpreting these data, however, itis important to keep
`in mind that there is an inverse relaionship between socioeconomic
`status andobesity, especially among women. Women in lowersocio-
`economicclasses are much morelikely to be obese than thosein higher
`socioeconomic classes. This association reduces, but does not elim-
`inate, the racial differences in the prevalenceof obesity. Whether the
`remaining racial differences in the prevalence ofobesity are due to
`genetic, constitutional, or social factors not related to incomeis not
`yet clear.
`
`Definition
`The National Institutes of Health/NHLBI report entitled “Clinical
`Guidelines on the Identification, Evaluation and Treatment of
`Overweight and Obesity” provides clear, scientifically based defini-
`tions of overweight and obesity, Body mass index (BMI) is now the
`recommended means to categorize weightrelativeto height foradults.
`Body mass index is calculated asweight (kg) divided by height squared
`(m’). To calculate BMI using pounds andinches, the formula is mod-
`ified as follows: weight (pounds)/height(inches)? x 703. The weight
`classifications according to BMI are summarized in Table 233-1.
`Individuals whe are overweight (BMI 25.0 to 29.9) may or may not
`be overfat, Some men may be overweight becauseofincreased muscle
`mass, which isa straightforward clinicaljudgment. Although in general
`the risk ofdeveloping weight-related health problemsincreases with
`a BMIgreater than 25, the guidelines point outthat intervention or
`discussion of weight issues with the patient may not be necessary for
`overweight adults who are entirely healthy and/or are not overfat. On
`the other hand, some individuals in the BMI27 to 29,9 range develop
`serious metabolic complications ofobesity that could be expected to
`improve with weight loss. These individuals are candidates for more
`aggressive treatment, including pharmacotherapyif needed.
`The risk of comorbidities increases considerably once the BMI
`increases above 30, the level at which obesity is diagnosed. Obesity
`is divided into three classes, also depending upon BMI. Treatment
`approaches maydiffer for those who are overweight andfordifferent
`classes ofobesity. For example, current Food and Drug Administration
`(FDA) guidelines indicate that pharmacotherapycan be adjuncttreat-
`ment for any class of obesity, even if medical complications are not
`present. Although some would argue that treating obese patients
`without medical complications is a lowerpriority than treating those
`with medical complications, familiarity with the guidelines is impor-
`lant; supervisory agencies and third party payers use them to deter-
`mine whois eligible for treatment benefits. Extreme obesity (BMI
`In one sense,the etiology of obesity can be considered simplisti-
`>40) is one of the key features that would promptconsideration of a
`cally; if energy intake exceeds energy expenditure, and if lean body
`patient for bariatric surgery when medical treatments have failed.
`mass remains stable, body fat must increase. Unfortunately, obesity
`Patients with class 2 obesity (BMI 35.0 to 39.9) may be considered
`is a much more complex issue, There are significant genetic/const-
`lor bariatric surgery if medical treatments havefailed andif severe,
`tutional susceptibility aspects to obesity that are heavily influenced
`life-threatening complications are present,
`by environmentalfactors, Evidence from family studies and studies
`The use of BMIto define overweight and obesity is an improve-
`of twins strongly supports the concept that within a given environ-
`ment over previous ideal weight
`tables, which were based on
`ment, a significant portion of the variation in weightis genetic. That
`height/yeight percentiles of individuals applying for insurance. In
`said, however, the tremendous increase in the prevalence of obesity
`addition to using BMI, the NHLBI Guidelines recommendusing the
`in the UnitedStates overthelast several decades can hardly beascnibed
`Waist circumferences as anotheroffice assessment tool that can help
`to mass changes in human DNA.
`with the treatment decision making process. A “large” waist cireum-
`GENETICASPECTS. Thereis strong evidence fora hereditary tendency
`lerence (greater than 102.cm or 40 inches for men and greater than
`toward the regulation ofbody weight. Thesingle genedefects result-
`
`ing in obesity include a number ofclassic genetic syndromes such as
`
`Prader-Willi and Laurence-Moon-BiedL, Thereaderis referred to text-
`
`books on genetic disorders fora completelistand description ofthese
`
`conditions. More recently, extremely rare monogenicforms ofhuman
`
`obesity due to mutations in the leptin gene andleptin receptor gene
`
`have been described. Theresult is an actual or functional leptin defi-
`
`ciency,muchlike that seen in ob/ob or db/db mice, the animal models
`
`a heritedformsofhuman obesity
`due to mutations ofgenes that
`thatstimulatedthe discovery of leptin, There have also beenreports
`
`»pelite neuropeptide
`esis. Doubtless, reports ofsingle
`muilonsasocateihanaobesitywillcontinueloappeary
`
`
`r,
`theoverwhelming malovity of cases of human obesi
`‘hecombinationofpolygenic susceptibilitytraits and
`
`
`al conditions.—
`
`
`Etiology
`
`a
`
`MPI EXHIBIT 1129 PAGE 3
`
`
`
`i
`
`Weel
`
`-om’
`
`TT
`
`I
`
`i
`
`
`witycan ebroadlyeeane
`eredacta aedworkandtheaetiy.
`-
`nd spotls
`employ™ able that allow ONE 16 eal
`an itiesinclude widely asidual’s weightas Well ag
`4340|Chapter 233 Obesty A numberof environmental slips
`ci
`:
`ise (fitness
`rise act!
`.
`ed on ,‘ch they&?gage. Unfortunately
`e-like effects on body weight regula’
`Noneneten ing:
`ities of daily V 5giture bas’
`: ptible to obesity-related fe
`canis enigA
`inexertectedtohaveApts.
`can result in long-term, Bet
`i
`id
`the
`pe
`and the tendency to he susce
`1
`Qo ed rauon thaobesity and other health prob.
`period on subsequent weight and hea pas aeeaial ii caeeatl?
`. development exercise regularly doesnotappear
`undermutrition 11 the last trimester© PE a uit obesity
`Me ut ikely that a changeitt exercige
`ostnatal period results In @ decrease
`8 Ath rite
`5 i¢ causil
`the increase in obesity,
`fiafortunately, the low birth weight that is Se en ate
`eeNeesSekaasoInceeaseTh adulthood. In
`a hh ea) activity is contributing to the
`se tolerance, and
`ca
`’
`d
`sina
`E
`ercise component that |s
`ee“undernutrition limited to the first te Beeata
`“tr is likely the none*
`To the extent
`nancy1s associated with an increased probabi ity oat ae Sees
`,
`Oo
`expended in nonexercise activ.
`Other early “environmental”effectsare that infants of
`ia dash i
`measure the energy
`1
`ent physical activi
`xing.
`vious that emp See systems in i
`itis difficult to
`tend to be fatter than those of nondiabetic mothers, ae Ae
`diabetic mothers have a greater prevalence of ae whe ae i
`h it set
`more au
`t
`insdecreased ait Seeite data in this regard. One estj-
`5 to 19yearsold, independentoftheir mother’0) ear a a
`intrauterine exposure to the diabetic environmentak ee
`ace, there
`and 1992, energy expenditure
`TReats that
`pe 50 kcal/day. The additional
`increased risk ofdiabetes mellitusandobesity in the o spring. rt
`the issue ofthe genes versus the environmentas regards obest yan
`at work decreasedBY oece that timehave likely further reduced
`metabolic complications of obesity1s blurred in the intrauterine %
`changes in the wor pia
`se,
`é
`‘itt
`perinatal time intervals. One ofthe striking and worrisome mse
`employment physical activily:
`exercise physical activity, the activi:
`of these metabolic effects is not only the long-term effects om the
`The pine! componentdifficult to measure. A paneobi
`individual's weight regulation and health, but the suggesuion that
`nesofdaily Nea eg.drive-through foodand banking,ec ators,
`these traits can be
`passed on to future generations,
`CONTRIBUTORS. Few wouldarguethat there have been
`Eatenbaie e-mail, on-lineshopping) havebeen introducedinto
`dramatic changes in the environment over the last 50 years. These
`remotesomenvironment. Each of these further reduces the energy
`changes promoted a reduction in the amountofphysicalactivity that
`De a xpend to get through the day. Again, there are few
`Americans undertake. In addition, alterations in the food supply
`ST ch of a change has actually occurred,
`have either increased or failed to allow the expected decrease in
`assess how mu
`u
`|
`i
`Secanola in daily walking tps and an increase in daily
`energy intake that would be needed to match the reduced energy
`tri
`ile
`ted,
`automobile trips has been documen
`:
`;
`;
`Perhaps because it is easier to assess, information as to how-dif-
`expenditure.
`;
`Food. A numberofenvironmentalfactors can influence food intake
`ferences in sedentary activity (television watching, video games,and
`(Table 233-2). Consuming energy-dense loods resultsin greater energy
`computer use) relate to obesity 1s more readily available. Thereis
`intake, because many adults respondto the volumeof food taken in
`rather than the energy contentoffood.This factor likely accounts for
`compelling evidence that more time spent in sedentary pursuits is
`the association between high-fat diets and excess body weight, many
`associatedwith anincreased risk ofoverweightand obesity,Thestrik-
`high-fat foods are also energy dense. When humans consumediets
`ing aspect to thesestudies is that the adverse effect of sedentary activ-
`that are high in fat but low in energy density, energy intake is not
`ities is independentof participation in traditional exercise activities.
`greater than would be expected based on the energy density of the
`Understanding the contributions of decreased work-related
`foods. Larger food portionsize has also been shownto increase food
`physicalactivity, decreased activity of daily living, and increases in
`intake. Given the trend in the United States to serve larger portions
`sedentary behavior can help the physician working with thepatient
`of food and beverage, this could be a contributing variable toward
`to uncoverpatterns that may relate to weight gain.
`obesity, Foodvarietycanalso affect energy intake. An increasedvariety
`In summary, there are clearly dramatic changes in Western envi-
`of entrees, sweets, snacks, and carbohydrates in the diet is associated
`eae that are conspiring to bring out tendencies toward obesity
`with an increaseinbody fatness and food intake. In contrast, an increase
`Eareiceconan
`in variety of vegetables available does notresult in an increased food
`intake and isnot associated with increased body fatness. Other factors
`obese patients identify vttch% riers a Baeae
`that may have broad population effects in the United States is the
`contributing to the proble
`aaah these environmental factors are
`reducedcosts of foodrelative to increased availability and palatabil-
`problem and develop plans for intervention.
`ity of foods.
`Several individual factors may also influence how the properties
`of food affect energy intake. Individuals vary with respect to their
`dietary restraint (the tendency to consciously limit food intake to
`Sey their feelings of hunger, or their disinhibition (the
`tendency to overeat opportunistically). {t has been proposed that
`interindividual differences in these factors may modify how [ood
`variety, portion size, and so on affect the eating profile.
`In additi
`to the environmentalinfluences on food consumption, there are ka
`the effects of the social context under which food is consumed and
`
`the emotional oftheindivistate
`
`staitified state of
`the individual. These effects are not yet well
`
`
`
`NutritionalDiseases
`
`
`
`:
`
`via ¢
`
`Che
`
`<
`capotemeta
`UNConscious processes:
`-
`lisi
`ary meansby 8enerallystored.astrigly®
`pri
`€S.
`:
`expands is to incr
`prim
`;
`[
`t
`hypertrophy). Thisensamountoffaeeadipose tissuemas
`owever, because ay Sess can store on|
`in eachcell (adipodre
`Sufficientfatis da ate is an upper lin Y a limited amount of
`preadipocytes oa eventually Agere the size offat cells:
`ue. Someadults sane stfomovascylay are recruited| ~
`Weightmorefra.’ *4!Pocytes m componentofadip
`isslowl,
`iSevidence thantPocyteh
`Ore readily than othe
`wlybutconti
`Ladip
`yperplasia than fromhyper
`invously
`he;
`u
`i
`suirpris:
`akanearnUTEOverAlthoughhsmay
`thoughtwe HennHelpate emphaa el §CtiVilies ina ee yey
`tu
`Wabout adipose 1 es
`that much of what Aance
`be incorrect.
`MPI EXHIBIT 1129 PAGE 4
`
`OSe tiss
`
`Ussue
`
`MPI EXHIBIT 1129 PAGE 4
`
`
`
`ENERGY INTAKE
`
`
`
`saspesiq(2U0nLINN
`
`Chapter 233 Obesity|1341
`st
`tin, a protein secreted by adipose ti
`corerows system effects on food intake aswella
`nantleptin resulted in
`a remarkable reduction in excessive hunger
`f cent snysiologicactions. led to the hopethat the problem
`andsignificantfat loss.
`In contrast, treatmentof overweightpatients
`:
`I
`5 onlation had been solved. The leptin-deficient animal
`with recombinant leptin did not show weightloss, despite achieving
`peak serum leptin concentrations greater than 30 times basallevels,
`ofweight
`the ob/ob mouse, ts severely obese, hyperphagic,
`Wey best sexually immature and has low ley
`In animals, leptin plays an important role in modulating the hypo-
`els of spon-
`fr
`gl
`On
`"
`s
`‘
`paabi2 dministering leptin to this
`thala mic-pituitary response to undernutrition and serves a protec-
`animal corrects all of
`tive function, Humanstudies are necessary to confirm this observation.
`ifs acntioned seea |
`esi
`Several ofthe observedeffects of exogenousleptin in ob/ob mice were
`ere”
`goesleptin play in human obesit
`y? Reports indicate
`hot observed in the single case of human leptin deficiency treated
`al role i individuals with increased body
`fat have high plasma
`with leptin. In summary, the discovery of leptin has been an impor-
`, julyrations therefore, leptin deficien
`V
`cy
`is not
`nobesity. Since the discoveryof ene, ont Siaehie
`tantadvancein understandingthe biology ofobesity; however, defects
`conte
`in leptin secretion or inherited defects in leptin action do not appear
`ring of consanguineous parents, have been found to
`to be the cause of even a tiny fraction of haman obesity.
`a peo waileptin deficiency; they were hyperphagic and severel
`veangenman leptin deficiency must be extremely rare, Some
`ecprac
`MNgenetic obesity (the db/db mouse andfa/fa rat) have
` nodels receptors, making them unresponsiveto leptin. These
`wv ep’ Mjsed the possibility that human obesity, rather than
`rat ion ofleptin deficiency, is a state ofleptin resistance
`ea ote human with a defective leptin receptor gene has
`pons4. itappears that peeae ae to leptin receptor
`;
`signaling genetic abnormalities)
`is extremely ra ;
`es (or 8iecied aboutthe physiology ofleptin in bones
`uch .ted in a diurnalfashion that appearsto be regulated by
`pti ={insulin and glucose on adipocytes. Leptin secretion can
`ed by30 to 40% with briefperiods of overfeeding (prior to
`esinbodySaaesseeby aveinHedges to
`rfeeding
`t
`result
`In significant changes in
`cage
`dsoa Thee rapid and substantial shifts in leptin pe
`pedSeetially accountfor a large portion ofthe variability in
`iatpeeFystrongrelationship between percentage ofbodyfat and
`iesetconcentrations. Whenbloodis collected undercarefully
`oralcircumstances, there is a very strong relationship between
`wo
`leptinconcentrations and percentageofbodyfat (Fig. 233-1).
`there is no difference in the relationship betweenleptin andper-
`wniage of body fat between women and men. Thus,the assertion
`dnt leptin resistance is present in women and in humanobesity is
`wi logical; if the normalbiologic Tesponse to increased bodyfatis
`
`messed leptin secretion, hyperleptinemia merely becomesadiffer-
`Table 233-3 ¢ SUGGESTEDBIOLOGICMODULATORS OF
`aidefinition offatness/obesity. Only whendeficiencyis present does
`FOOD INTAKE
`.
`isphysiology relate to the developmentofobesity.
`
`low or absentleptin results in extreme hunger.Treating patients
`PERIPHERALSIGNAL
`wih congenitalleptin deficiency with physiologic doses of recombi-
`Vagal
`ern
`vii
`(ey ry oY
`cholecystokinin
`==
`"
`tre il \|
`‘ApolipoproteinA-TV CONTRET
`owl
`Insulin —
`Y:
`TORT] n=) ane
`t
`Glucagon-likepeptide1
`aii a |
`Other glucagonrelated peptides (=)
`Leptin
`Pe
`ae ee
`fFwhealspon:
`rm.
`CLL TEPT ;
`dient
`onmam
`oeeta,a cola |
`
`oe 4 Ole
`iin
`vy mmc
`
`; & stimulatesfoodintake, _
`_
`. (-) inhibits foodintake._
`es al
`
`
`
`Muchhasbeen learned aboutthebiologicregulation offoodintake,
`mostly from the study of animal models. There area series of periph-
`eral “satiety” signals that act to inhibit further food intake at some
`pointduring meal consumption. Someofthe signals reach the brain
`via the vagus nerve and somevia the systemic circulation. Examples
`of the proposed humoral factors modulating appetite are listed in
`Table 233-3. Many of the compoundsare gut- or pancreas-derived
`hormones (cholecystokinin, glucagon-like peptide 1, insulin, and
`perhapsotherglucagon-related peptides or gut peptides) or peptides
`(apolipoprotein A-IV, secreted with chylomicrons). The signals are
`thoughtto be triggered both by mechanicalstimuli (e.g., the fullness
`of the stomach)and by the presence of nutrients in the jejunum and
`ileum. It has also been suggested that the drop in leptin concentra-
`tions atnight may allow the evolution ofhunger the followingmorning.
`The central nervous system regulation offood intake isalso better
`understood. A series of neuropeptides and monoamines have been
`identified that have either anabolic (increased food intake with or
`without decreased energy expenditure) or catabolic (decreased food
`intake with or without increased energy expenditure) properties. A
`list of these compounds is provided in Table 233-4. Understanding
`
`Table 233-4 » CENTRAL NERVOUSSYSTEM MO!
`
`OF ENERGY BALANCE
`
`|
`Nay,
`
`We?and eons relationship between serum leptin concentrations(log.
`by bled tromJenee®” of body fat in 43 lean and obesemen andwomen.
`ioofplasm Hensrud D, O'BrienPC, etal:Collectionand—
`ey thas, @]
`leptin concentration datainhumans,ObesRes
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`MPI EXHIBIT 1129 PAGE 5
`
`MPI EXHIBIT 1129 PAGE 5
`
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`e
`
`expenditureof
`
`: Theen iit HuceaeweWork
`perv duct ol pecause therestimati0g the energyAe
`the am
`js not Tuc)
`vars
`1342.|Ghapter 233 Obes!)
`es
`for&, common tO Express
`very of thera-
`mayallowthe disco
`i
`anor
`:
`i
`3 whichis a multipleof
`the process of appetite regul
`inhibit or stimulate eitheranabolic
`valen’
`jdividual’s RMRis 1 keal/nn
`that will selectively
`peutic agents
`tem pathways:
`ich Highly trained athletescay
`fan in
`or catabolic central nervous Sys
`c
`oY ~xtendedperiods, =
`efor limited aete lower
`‘d als canon
`ctrel
`‘r
`refers to the ars
`number
`ry indiv!
`ork capac
`f oxygen that can Deco
`ount of
`endous variabilityin peak
`trem
`hat— beexpended. narsolely, related to howmuchang
`ed.
`;
`largely,
`DY
`work aa ol activity 5 pererstandingthecapacitylorplis
`Pertantconceplin
`ions) is the lactate
`tires
`Id.
`, aeeetandthusexerciseer ht rras the level at which exercise
`Tet
`hreshold can Sabie thatitcannot be maintainedmuch
`Thelactate t
`ee
`asamre—
`i
`hecomeso une
`an
`relates to the Pp er
`tise in
`lieThe biochemical SNeae observed. The lactate threshold
`.
`a
`bloodlactate ead 90% of an individual'speakworkSpasity
`may Tange Te lactate threshold closer mu her rates far lq
`*
`Training raises
`individuals to work at
`higne
`ily
`ki
`ger
`load, andthsese sedentary individuals Yeries
`eaeiatarequite low (sometimes oeoeents with a
`pinhe threshold can be even lower in obese P
`'ype
`an
`diabetes.
`_related activities) is commonlycon-
`Exercise (fitness- and sports ae
`sical activity thermogenesis.
`i
`main component of phy.
`;
`i
`Treeamountofenergycanbeexpendedinrelativelybrief
`periods in fit ©dividuals, most adults do not exercise at high levels
`cient duration to expenda large amount of energy. Thus,
`aniCTs solely on “exercise” as the main componentaf
`physical activity energy expenditure, it is important to consider the
`energy costs of nonexercise activily.
`;
`-
`Nonexercise activity thermogenesis (NEAT)is the caloric expense
`ofperformingall activities other than exercise. Therange ofobserved
`NEAT undercontrolled (metabolic chamber) conditions has been from
`less than 100 up to approximately 800 kcal/day. There is probably a
`muchwiderrangein free-living individuals. NEATts nota static com-
`ponentof daily energy expenditure. It has been shown that NEAT
`can increase in responseto increased food intake in an unconscious
`manner, In fact, modulation of NEAT can bea significantfactorthat
`acts to stabilize weight despite variations in food intake. Low levels
`of NEAT have been reported to predict future weight gain in
`some populations. There is virtually no information as to what the
`regulatory systems are that stimulate or inhibit NEAT.
`
`:
`
`
`
`NutritionalDiseases
`
`ENERGY EXPENDITURE
`es widely, from less than
`nditure in adults vari
`Dey ay nae than 5000 kcal/day, with larger, more P
`rey
`needs. Typical i
`400 keal/day to mor
`cally active ivdividuals havingthe greatest ene
`BY
`1) metabolic
`daily energy expenditure ts divided into resting (or basa
`and physical activity energy
`rate,
`the thermic effect of food,
`The basal metabolic rate (BMR)is the energy
`expenditure.
`veal
`ke, in the overnight postabsorplive
`diture of lying still at rest, awa
`"
`or to arising
`ed ae BMR fs measured after awakening but prt
`lic rate (RMR)is similarly defined but
`ed, The resting metabo
`For most seden-
`HaatSieastired before arising frombed.
`tion of energy
`tary adult Americans, the RMR represents the major por
`from less than 1200 to more
`expended during the day and may range
`ly 80%) of the BMR can be
`than 3000 keal/day, Most (approximately ©
`related to the amountoflean tissue an individual has.
`at the same
`Notall components oflean tissue consume oxygen
`relative rates. Visceral, or splanchnic bed, tissues account for approx-
`imately 25% ofresting metabolic rate buta much smaller propornon
`ofbody weight. The brain, which accounts for only a small percent
`ofbodyweight, accountsforalmost 15% ofRMR,Likewise, the heart
`(approximately 7%) and kidneys (approximately 5 to 10%) account
`for greater portions of resting energy needs than their relative con-
`tribution to body mass. In contrast, resting muscle makes up 40 to
`50% of lean tissue mass but accounts for only 25% of RMR. This
`changes dramatically with exercise, however; muscle can accountfor
`80 to 90% of energy expenditure during high-intensity exercise.
`Adipose tissue is a minor contributor to daily energy expenditure,
`consuming only approximately 3 kcal/kg/day.
`Although the vast majority of RMR can be accountedfor by the
`amountof lean tissue an individual has, there are also other, more
`subtle, influences on RMR.Age, gender (women haveslightly lower
`BMRs, even corrected for fat-free mass), and fat mass affect RMR.
`Slight changes in metabolic rate or BMR are observed during the
`menstrual cycle (luteal phase more than follicular phase). There is
`also evidence that heritable or family factors do influence BMR,
`accounting for as much as 10% ofinterindividual differences.
`There are both obligatory and facultative components to RMR.
`With an energy-restricted diet, significant reductions in BMRrelative
`to the amountof fat-free mass occur, Reductions in the production
`of triiodothyronine from thyroxineare thought to contribute to this
`phenomenon. Likewise, during brief periods of overfeeding, it has
`been found that RMR increases above that which would be expected
`for the amountof lean tissue present.
`_
`It has been proposed thatindividuals with BMRs lowerthan pre-
`dicted are atincreased risk offuture weightgain. Published data suggest
`thattherelative risk is small, and the clinical effort to identify such
`patients is not warranted. Measurementof BMR is sometimes help-
`fulin the evaluation ofpatients whoinsist they are unable to (oBe
`weight while following diets consisting of less than 1000 kcal/day,
`Almost withoutfail, their BMR is substantially greater than their
`reported food intake. This underscores the fact that most adults
`oh
`7
`Sat
`:
`;
`notoriously unreliable in assessing their own food intake.
`THERMIG EFFECT OF FOOD. Approxi
`!
`‘FOOD.
`Approximately 10% of the
`ooisexpendedin theprocessofdigestion,secretiontensa
`olism ee nutrients. There is significantinterindividual variabilit
`in
`thisvalue,rangingfrom alowofapproximately5% to ahigh ofssnhos
`imately 15% of meal calories that are “was
`_
`wasted” in the postprandial
`interval. The thermic effect of a mea
`lis related to the carbohydrate
`and protein caloric content of the m
`aas fat content haslittlestim-
`ulatory effect), Both obligatory an
`acullative components oft
`aay The obligatory ee
`thermiceffect of food have been i
`nents no doubtreflect the energy
`ergy
`costs of
`digestion, abs
`casetata, Approximately 60 to 70% ofthe peess
`5 obligatory, and the remaining 30 to 40% is facultative ther-
`Mogenesis, The twofactors though L to
`play a role in the facultative
`component of the thermic effect af food
`are the postprandial insulin
`pein ana activation of the 5
`ympathetic nervous system, The
`€ elleet of food j
`humans, but there ieee
`ower in insulin-resistani/o
`SereApr have been no reported links between tee
`Ogenesis and future obesity.
`
`Secondary Causes of Obesity
`MEDICATIONS. A growi
`Hg numberof medications cause weight gan
`in some or most of th
`
`i
`
`oaches,
`
`toateweony for the underlying condition.
`“m
`patientshave anunderlyingdisease
`can explain their obesi